Individual optimization: Mechanisms shaping the optimal reaction norm

In general, optimal reaction norms in heterogeneous populations can be obtained only by iterative numerical procedures (McNamara, 1991; Kawecki and Stearns, 1993). We consider two particular, but biologically plausible and analytically tractable cases of individual optimization to gain insight into the mechanisms which shape the optimal reaction norm of fecundity in relation to an environmental variable or an individual trait. In the first case, we assume that the quality of the environment (e.g. food abundance) or the quality of the individual (e.g. body size) is fixed during its entire life; it may also be a heritable individual trait. In the second case, individual quality is assumed to change randomly such that the probability distribution of quality in the next year is the same for the parent and for her offspring. For these two cases, we obtain analytical expressions for the shape of the optimal reaction norm, which are heuristically interpretable in terms of underlying selective mechanisms. It is shown that better quality may reduce the optimal fecundity. This outcome is particularly likely if better quality increases a fecundity-independent factor of parental survival in a long-lived species with fixed quality. This revised version was published online in July 2006 with corrections to the Cover Date.     

DIAGNOSTIC SELF‐TESTING: AUTONOMOUS CHOICES AND RELATIONAL RESPONSIBILITIES

Diagnostic self‐testing devices are being developed for many illnesses, chronic diseases and infections. These will be used in hospitals, at point‐of‐care facilities and at home. Designed to allow earlier detection of diseases, self‐testing diagnostic devices may improve disease prevention, slow the progression of disease and facilitate better treatment outcomes. These devices have the potential to benefit both the individual and society by enabling individuals to take a more proactive role in the maintenance of their health and by helping society improve health and reduce health costs. However, the full implications of future home‐based diagnostic technology for individuals and society remain unclear due to their novelty. We argue that the development of diagnostic tools, especially for home use, will heighten a number of ethical challenges. This paper will explore some of the ethical implications of home‐based self‐testing diagnostic devices for the autonomous and relational dimensions of the person. This will be facilitated by examining the impact of diagnostic devices for individual autonomy, for the delivery of accurate diagnosis and for the personal significance of the information for the user. The latter will be examined using Charles Taylor's view of personhood and his emphasis on human agency and interpretation. While the ethical issues are not necessarily new, the development of home‐based self‐testing diagnostic devices will make issues regarding autonomy, accuracy of information and personal significance more and more demanding. This will be the case particularly when an individual's autonomous choices come into conflict with the person's relational responsibilities.     

Colchicine after-effects on the absorption and utilisation of phosphates and nitrates by mycelial felts of Cunninghamella sp.

Summary Colchicine at 5 and 10 p.p.m. increased both phosphorus uptake and incorporation into organic forms (nucleoproteins or other simpler organophosphorus compounds). Continuous supply of colchicine at 20 p.p.m., almost checked phosphorus uptake during the second 24 hours of the experiment.The absorbed nitrates were utilised through the classical reduction steps. It appears also that colchicine had an inhibitory effect on the nitrite reductase that increased by increasing the concentration of the drug. Continuous supply of colchicine at its highest concentration (20 p.p.m.) checked completely the protein building during the second 24 hours of the experiment, though nitrate absorption continued; a phenomenon that caused the accumulation, in the tissue medium systems, of large amounts of peptide nitrogen.The mechanism of nitrate reduction as affected by colchicine treatment was fully discussed.     

Colchicine after-effects on the absorption and utilisation of sucrose by Cunninghamella sp.

Summary Colchicine had no significant effects on the rate of growth of Cunninghamella when administered in 5 p.p.m. concentration; at 10 p.p.m., it induced a slight increase, while at higher concentrations it lowered the dry weight. Pretreatment with colchicine, during the fungal growth induced a persistant activation of hexose phosphorylases, particularly fructose phosphorylase; more promenantly by the continuous supply of the drug than during the recovery on Richard's medium; a phenomenon that might be partially or wholly alleviated by transfer of the treated mats to Richard's solution alone. In all cases the CO₂ output of the treated samples was unaffected by the drug except at higher levels (20 p.p.m.).Colchicine treatment favoured the accumulation of polysaccharides; the rate of accumulation depended entirely on both the dose and duration of administration. Furthermore, lower concentrations of the drug favoured nucleoprotein formation but had no effect on nucleotides while the higher concentrations reduced both fractions: a phenomenon that persisted whether the tissues were continuously fed with the drug or recovering on nutrient solution alone.The changes in the metabolic pathways of the absorbed sugars have been thoroughly discussed.     

Infliximab substantially re-silenced Wnt/β-catenin signaling and ameliorated doxorubicin-induced cardiomyopathy in rats

The release of inflammatory cytokines, namely tumor necrosis factor-α (TNF-α), plays an important role in the pathogenesis of cardiomyopathy. TNF-α increases in plasma and in myocardium of heart failure patients. We aimed to investigate the role of TNF-α inhibitor (infliximab; IFX) in regulating dilated cardiomyopathy (DCM) induced in rats. DCM was induced in rats by doxorubicin (DOX; 3.5 mg. kg⁻¹, i.p) twice weekly for 3 weeks (21 mg. kg⁻¹ cumulative dose). DCM rats were treated with RPL (1 mg. kg⁻¹ orally, daily), IFX (5 mg. kg⁻¹; i.p. once) or their combination for 4 weeks starting next day of last DOX dose. Echocardiography was conducted followed by a collection of blood and left ventricle (LV) for biochemical and histological investigations. DCM rats revealed deteriorated cardiac function (increased CK-MB activity, LVIDs, LVIDd, ESV, and EDV, while decreased EF% and FS%), hypertrophy (increased HW/TL, β-MHC, and α-actin), inflammation (increased IL-1β, IL-6, and TNF-α). The activation of Wnt/β-catenin along with increased gene expression of RAS components (RENIN, ACE, and AT1) were evident. LV architecture also revealed abnormalities and some degree of fibrosis. Treatment with RPL and/or IFX suppressed TNF-α and consequently improved most of these parameters suppressing Wnt/β-catenin/RAS axis. Combined RPL and IFX treatment was the best among all treatments. In conclusion, Wnt/β-catenin/RAS axis is implicated in DOX-induced cardiomyopathy. The upstream TNF-α was proved for the first time in-vivo to stimulate this axis where its inhibition by RPL or IFX prevented DCM. Targeting this axis at two points using RPL and IFX showed better therapeutic efficacy.     

Design,Synthesis, Anticancer Evaluation and Molecular Modeling Studies of New Thiazolidinone-Benzoate Scaffold as EGFR Inhibitors,Cell Cycle Interruption and Apoptosis Inducers in HepG2

Synthesis of new anticancer candidates with protein kinases inhibitory potency is a major goal of pharmaceutical science and synthetic research. This current work represents the synthesis of a series of substituted benzoate-thiazolidinones. Most prepared thiazolidinones were evaluated in vitro for their potential anticancer activity against three cell lines by MTT assay, and they found to be more effective against cancer cell lines with no harm toward normal cells. Thiazolidinones 5 c and 5 h were further evaluated to be kinase inhibitors against EGFR showing effective inhibitory impact (with IC₅₀ value; 0.2±0.009 and 0.098±0.004 μM, for 5 c and 5 h , respectively). Furthermore, 5 c and 5 h have effects on cell cycle and apoptosis induction capability in HepG2 cell lines by DNA-flow cytometry analysis and annexin V-FITC apoptosis assay, respectively. The results showed that they have effect of disrupting the cell cycle and causing cell mortality by apoptosis in the treated cells. Moreover, molecular docking studies showed better binding patterns for 5 c and 5 h with the active site of the epidermal growth factor receptor (EGFR) protein kinase (PDB code 1M17). Finally, toxicity risk and physicochemical characterization by Osiris method was performed on most of the compounds, revealing excellent properties as possible drugs.     

Studies on the mechanism of action of sulfanilamide on mycelial felts of Rhizoctonia solani

Summary Sulfanilamide induced strong inhibitory effects on the growth, respiration and carbohydrate synthesis by mycelial felts of Rhizoctonia solani. The possible reasons for such inhibitory effects are discussed.The inhibitory effects of sulfanilamide were almost completely alleviated by the inclusion of p-aminobenzoic (PABA) acid in the culture medium of the fungal mats. R. solani normally produces certain amounts of PABA and its growth and metabolism is inhibited in presence of excess of it.